Many of the pharmaceutically active ingredients currently considered useful have a short biological half life and need to be administered several times a day. Should the administration frequency of such drugs can be decreased, it will not only lessen the burden on patients but also enhance compliance of the patients and bring about higher treatment effects. For this end, it is necessary to control release of a pharmaceutically active ingredient in such a manner that an effective concentration in blood can be maintained over an extended period of time.
In this regard, release of a drug at a constant rate (zero order dissolution) irrespective of the concentration of the drug which is in the dosage form as shown in FIG. 1a will be most ideal.
Such ideal zero order drug release maintains the concentration of a drug at a constant level in the tissues, thus allowing the drug concentration in blood to stay at a safe level. In particular, this release method is most effective for a drug which causes side effects even at a concentration a drug administration can easily achieve. In addition, the administration frequency can be decreased, since efficacy of the drug can be maintained for a long time. In contrast, a dissolution with decreasing rate with time, such as that shown in FIG. 1b and presently seen in many preparations, is called a first order dissolution.
Japanese Patent Unexamined Publication No. 23814/1988 reports a sustained release pharmaceutical composition for oral administration having almost zero order release property. According to this gazette, the composition has, in the main construction, a core material comprising at least a 20% derivative cellulose as a gelling agent, a drug homogeneously dispersed in the gelling agent and optionally a pharmaceutically acceptable excipient, and a coating of a permeable, slowly-dissolving derivative cellulose polymer applied to the core material. As the gelling agent, usable is, for example, hydroxypropylmethylcellulose and as the coating polymer, usable is, for example, a dispersion of ethylcellulose (aqueous dispersion). According to the examples therein, however, the zero order release continues for the first 10 hours or up to 85% dissolution at most, and it is not verified if the dissolution remains zero order up to 100%. The reason therefor is that the ethylcellulose for the coating layer has poor binding property when used as an aqueous dispersion and the core swells as the gellation proceeds, to the point that the coating layer is finally broken.
Besides the aforementioned, there are many controlled release (sustained release) preparations being studied, such as those shown in the following.
A sustained release preparation comprising rapidly dissolving granules and slowly released granules in combination in, for example, a capsule, such as the one for rhinitis achieves the sustained release according to a preparation design in which the rapidly dissolving part is dissolved immediately after administration and then a predetermined amount of a drug is released gradually from the slowly released part. In this case, the defect is that the production of the granules to be released slowly with time should be modified every time a drug to be contained changes, as can be seen in Japanese Patent Unexamined Publication Nos. 103012/1987, 197433/1989 and 230513/1989. The release of a drug from globular sustained release granules as described does not make a zero order release, since dissolution rate slows down with time due to the decreasing concentration gradient of the drug contained in the granules, as a result of the dissolution of the drug through an outer layer without destruction of the granules. This type of preparation mostly releases drug by allowing same to dissolve through a film which is formed on a spherical granule containing the drug and which does not dissolve in a digestive juice. For this mechanism, this type of preparation cannot be applied to a drug slightly soluble in water. While there are other types of dissolution which are similar to the one mentioned above, such as simple matrix type dissolution wherein a drug is encapsulated in a wax or a water-insoluble coating agent and gradually dissolved through the outer layer or the drug is dissolved along with the dissolution of the outer layer, such preparations hardly achieve a zero order release but rather a first order release, since the drug dissolution area becomes smaller as the drug dissolves out.
The hydrophilic polymer matrix preparations recently drawing attention have a preparation design in which a drug dispersed in a hydrophilic polymer is diffused through the gel formed by the polymer by the absorption of water in the digestive tract, and released from the gel layer. For example, EP-B-282,111, Japanese Patent Unexamined Publication No. 128917/1989 and SE-A-8008646-5 disclose controlled release of a pharmaceutically active ingredient by the use of a gelling polymer. The swelling type sustained release tablets using a hydrophilic polymer comprise those wherein tablets simply absorb water, swell (into a spherical shape in this ease) and disintegrate from the outer layer where dissolution begins gradually, and those wherein a drug dissolves out beginning from the outer layer to the inner layer while maintaining the swollen, spherical shape. The significant defect is that they can be prepared into first order dissolution preparations only, since the dissolution area becomes smaller as the drug dissolves out and the concentration of the drug in the matrix develops a gradient.
When a semipermeable film, a water-swellable film such as polyacrylate or an enteric-coated film generally used for sustained release preparations is used, possible swelling is as conventional as the one shown in FIG. 3, wherein a tablet gradually absorbs water from the entire surface through the film so that it swells into a sphere, or the film is dissolved in a gastric juice so that the tablet absorbs water from the entire surface and swells into a sphere, with the result that a zero order release cannot be attained. When an enteric coating is mainly used, administration of the tablet to the patients suffering from achlorhydria may be difficult.
When using a prior art technique, formulation and production method should be greatly modified according to the characteristics of the pharmaceutically active ingredient to be administered. For example, Japanese Patent Unexamined Publication No. 1614/1986 teaches triple coating of different types of pH-dependent films to achieve sustained release. The above-mentioned Japanese Patent Unexamined Publication No. 23814/1988 teaches the use of a buffer according to the pharmaceutically active ingredient.
Besides the aforementioned, many sustained release preparations have been developed, which basically are, generally-classified, of simple matrix type inclusive of those having a hole in the coated film, of membrane permeable type to allow dissolution of a drug through a semipermeable film, of water-swellable matrix type, or of disintegration or dissolution type, and at the present moment, there has not been provided a zero order sustained release tablet which is applicable to both water-soluble and slightly water-soluble drugs.